The use of polymers to deliver chemotherapy to brain tumors has effectively prolonged survival in animals and humans. Nevertheless, there is little information on the optimal characteristics of drug/polymer formulations to enhance delivery of agents in the brain. During the previous funding period we developed new experimental techniques and mathematical models for studying the transport and clearance of agents released from polymers into the brain. By comparing drug concentration maps determined by quantitative autoradiography and MR imaging to models of drug transport, we were able to determine effective distances for drug penetration into the brain following release from a polymer and to relate drug concentrations in the brain to properties of the drug/polymer combination. We have also used our mathematical models to design novel chemotherapy drugs that have enhanced penetration in the interstitial space. Our results were used by other programs in the NCDDG to design new agents and formulate polymers to optimize delivery. The overall objectives of this renewal project, therefore, will build upon these advances. We will use our experimental techniques to determine the transport and clearance characteristics of anticancer drugs and macromolecules in normal and tumor-bearing animals. We will then use this information to design and synthesize novel agents with improved penetration through tissues and enhanced activity at the tumor site. To facilitate the design of brain tumor vaccines or adoptive immunotherapy strategies, we will use our techniques to examine the movement of cytokines and T cells in the brain. To accomplish these objectives, we will: l. study the diffusion and clearance characteristics of drugs in the normal brain and brain containing tumors; 2. use our mathematical models to explore the mechanisms of drug distribution and clearance in the brain, particularly focusing on complex drugs, multi-drug combinations, and the effect of fluid flows; 3. synthesize and characterize novel drug compounds with enhanced penetration through tissues; and 4. study the migration of activated lymphocytes in normal brain tissue and brain tumors. Our Program will interact with all of the other Programs of this NCDDG. We will continue to collaborate with Program l by correlating the pharmacokinetics and local distribution with drug efficacy in animal brain tumor models. We will examine the pharmacokinetics and local distribution from the best polymer formulations produced by Program 2 and Core B. We will provide these same Programs with guidance in polymer design, based on the kinetics and mechanisms of delivery determined from our experiments. We will continue to collaborate with Program 4 on the development of anticancer drugs that are specifically designed for intracranial delivery. We will work with Program 5 by identifying the mechanisms of cytokine and immune cell traffic following delivery to a local site.